The present invention relates to novel prostaglandin derivatives, pharmaceutically acceptable salts thereof and hydrates thereof.
Since prostaglandin (PG) exhibits various important physiological actions in a trace amount, the biological activities of a great number of natural PGs and synthesized PG derivatives have been investigated with the intention of a practical use as medicines and have been reported in many literatures and patents. Among them, Japanese Patent Kohyo Hei 2-502009 discloses a group of PG derivatives substituted with a halogen atom at the 9-position. Furthermore, PG derivatives having a PGD2-like agonistic activity are reported by K-H Thierauch et al., in Drug of the Future, vol. 17, page 809 (1992).
In addition, PGs have been not only reported on their various central nervous actions and but also clarified as to the intracerebral content, biosynthesis, metabolic pathway, their intracerebral localization and changes with growth or aging, and there has been taken an interest in the relation between sleep and wake by PGs. Among them, PGD2 has been known as an intracerebral humoral factor which controls the occurrence or maintenance of sleep, and it was made clear that the sleep induced by PGD2 in monkeys is undistinguished from their spontaneous natural sleep in brain wave or behavior (Proc. Natl. Acad. Sci. USA, vol. 85, pp. 4082-4086 (1988)), therefore this compound was expected as a new compound having a sleep-inducing action.
However, PGD2 derivatives including PGD2 are presently unpractical due to the problems concerning their intracerebral transition and stability. Furthermore, there has not been specifically reported about sleep-inducing action of PG derivatives other than PGD2 derivatives.
An object of the present invention is to provide novel PG derivatives having a PGD2-like agonistic activity and a sleep-inducing action.
As a result of the continued extensive studies, the present inventors have found that novel prostaglandin derivatives represented by the following Formula (I) achieve the above-objects, and thereby the present invention has been accomplished.
That is, the present invention is directed to a prostaglandin derivative represented by Formula (I): 
[wherein X is a halogen atom in the xcex1- or xcex2-position, Y is an ethylene group, a vinylene group or an ethynylene group, A is a group represented by the formula: O(CH2)n,
S(O)p(CH2)n,
O(CH2)qO(CH2)r,
O(CH2)qS(O)p(CH2)r,
S(O)p(CH2)qS(O)p(CH2)r or
S(O)p(CH2)qO(CH2)r 
(wherein n is an integer of 1 to 5, p is 0, 1 or 2, q is an integer of 1 to 3, and r is 0 or 1),
R1 is a C3-10 cycloalkyl group, a C1-4 alkyl-C3-10 cycloalkyl group, a C3-10 cycloalkyl-C1-4 alkyl group, a C5-10 alkyl group, a C5-10 alkenyl group, a C5-10 alkynyl group or a bridged cyclic hydrocarbon group,
R2 is a hydrogen atom, a C1-10 alkyl group or a C3-10 cycloalkyl group, and
m is 0, 1 or 2], a pharmaceutically acceptable salt thereof or a hydrate thereof.
Furthermore, the present invention is directed to a pharmaceutical preparation which comprises as an effective Ingredient the compound represented by formula (I), the pharmaceutically acceptable salt thereof or the hydrate thereof.
In the present invention, the vinylene group refers to a cis- or a trans-vinylene group. The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The C3-10 cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms, examples of which are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
The C1-4 alkyl-C3-10 cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms substituted with a straight or branched alkyl group having 1 to 4 carbon atoms, examples of which are a methylcyclopropyl group, a methylcyclohexyl group and an ethylcyclohexyl group.
The C3-10 cycloalkyl-C1-4 alkyl group means a straight or branched alkyl group having 1 to 4 carbon atoms substituted with a cycloalkyl group having 3 to 10 carbon atoms, examples of which are a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclohexylmethyl group, a cyclohexylethyl group and a cycloheptylmethyl group.
The C5-10 alkyl group means a straight or branched alkyl group having 5 to 10 carbon atoms, and examples of which are a pentyl group, a hexyl group, a heptyl group, an octyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 2,4-dimethylpentyl group, a 2-ethylpentyl group, a 2-methylheptyl group, a 2-ethylhexyl group, a 2-propylpentyl group, a 2-propylhexyl group and a 2,6-dimethylheptyl group.
The C5-10 alkenyl group means a straight or branched alkenyl group having 5 to 10 carbon atoms, examples of which are a 3-pentenyl group, a 4-hexenyl group, a 5-heptenyl group, a 4-methyl-3-pentenyl group, a 2,4-dimethylpentenyl group, a 6-methyl-5-heptenyl group and a 2,6-dimethyl-5-heptenyl group.
The C5-10 alkynyl group means a straight or branched alkynyl group having 5 to 10 carbon atoms, examples of which are a 3-pentynyl group, a 3-hexynyl group, a 4-hexynyl group, a 1-methylpent-3-ynyl group, a 2-methylpent-3-ynyl group, a 1-methylhex-3-ynyl group and a 2-methylhex-3-ynyl group.
Examples of the bridged cyclic hydrocarbon group are a bornyl group, a norbornyl group, an adamantyl group, a pinanyl group, a thujyl group, a caryl group and a camphanyl group.
The C1-10 alkyl group means a straight or branched alkyl group having 1 to 10 carbon atoms, examples of which are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a 2-ethylpropyl group, a hexyl group, an isohexyl group, a 1-ethylbutyl group, a heptyl group, an isoheptyl group, an octyl group, an nonyl group and a decyl group.
Examples of the pharmaceutically acceptable salt are salts with alkali metals (e.g., sodium or potassium), alkali earth metals (e.g., calcium or magnesium), ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, a tetraalkyl ammonium and tris(hydroxymethyl)aminomethane.
Preferable compounds of the present invention are those of Formula (I) wherein R1 is a C3-10 cycloalkyl group, a C1-4 alkyl-C3-10 cycloalkyl group, a C3-10 cycloalkyl-C1-4 alkyl group, a branched C5-10 alkyl group, a branched C5-10 alkenyl group, a branched C5-10 alkynyl group or a bridged cyclic hydrocarbon group. Further preferable compounds of the present invention are those of Formula (I) wherein X is a chlorine or bromine atom in the xcex1- or xcex2-position, R1 is a C3-10 cycloalkyl group, a C3-10 cycloalkyl-C1-4 alkyl group or a branched C5-10 alkenyl group, and R2 is a hydrogen atom or a C1-10 alkyl group.
Furthermore, Y is preferably a vinylene group or an ethynylene group, and more preferably an ethynylene group. A is preferably a group represented by the formula: S(O)p(CH2)n, S(O)p(CH2)qS(O)p(CH2)r or S(O)p(CH2)qO(CH2)r, and more preferably a group represented by the formula: S(CH2)n, S(CH2)qS(CH2)r or S(CH2)qO(CH2)r.
The compounds of Formula (I) can be prepared, for example, by the methods summarized by the following reaction scheme. 
In the reaction scheme, A1 is a group represented by the formula: O(CH2)n, S(CH2)n, O(CH2)qO(CH2)r, O(CH2)qS(CH2)r, S(CH2)qS(CH2)r or S(CH2)qO(CH2)r (wherein n, q and r are as defined above), A2 is a group as defined for A except for p=O. Yxe2x80x2 is an ethylene group or a vinylene group, R3 is a C1-10 alkyl group or a C3-10 cycloalkyl group, TBS is a tert-butyldimethylsilyl group, and X, Y, R1 and m are as defined above.
The above-mentioned reaction scheme is illustrated as follows:
(1) At first, a known compound of Formula (II) is reacted with 0.8 to 2.0 equivalents of a compound represented by Formula (III) or (IIIxe2x80x2) in an inert solvent (e.g., benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride or n-hexane) at xe2x88x9278 to 30xc2x0 C. according to the method of Sato et al. (Journal of Organic Chemistry, vol. 53, page 5590 (1988)) to stereospecifically give a compound of Formula (IV). Herein, the compound wherein Y is an ethylene group or a vinylene group (i.e., the compound wherein Y is Yxe2x80x2) can be obtained by a reaction using a compound of Formula (IIIxe2x80x2) at xe2x88x9278 to 0xc2x0 C., and the compound wherein Y is an ethynylene group can be obtained by a reaction using a compound of Formula (III) at 0 to 30xc2x0 C.
(2) The compound of Formula (IV) is reacted with 0.5 to 4 equivalents of a compound represented by Formula (V) or (VI) and 0.05 to 2 equivalents of a radical generating agent (e.g., azobisisobutyronitrile, azobiscyclohexanecarbonitrile, benzoyl peroxide or triethyl borane), if necessary, further using 1 to 5 equivalents of a radical reductant (e.g., tributyltin hydride, triphenyltin hydride, dibutyltin hydride or diphenyltin hydride) in an inert solvent (e.g., benzene, toluene, xylene, n-hexane, n-pentane or acetone) at xe2x88x9278 to 100xc2x0 C. to give a compound of Formula (VII). Depending on the situation, the compound of Formula (VII) can be also obtained by a reaction using 0.05 to 2 equivalents of a base (e.g. an organic amine such as triethylamine, diisopropylamine, pyridine or dimethylaniline, or a base resin such as polyvinylpyrrolidone, diisopropylamlnomethylxe2x80x94polystylene or (piperidinomethyl)polystylene) and, if necessary, using 0.01 to 0.5 equivalent of a bivalent palladium complex or complex salt (e.g. dichlorobis(acetonitrile)palladium(II), dichlorobis(benzonitrile)palladium(II) or palladium chloride) in an inert solvent (e.g., benzene, toluene, xylene, n-hexane, n-pentane or acetone) at xe2x88x9278 to 100xc2x0 C.
(3) The compound of Formula (VII) is reacted with 0.5 to 5 equivalents of a reductant (e.g., potassium borohydride, sodium borohydride, lithium tricyanoborohydride, lithium tri-sec-butyl borohydride or diisobutylaluminum hydridexe2x80x94BHT (2,6-di-tert-butyl-p-cresol) in an organic solvent (e.g., tetrahydrofuran, diethyl ether, ethyl alcohol or methyl alcohol) at xe2x88x9278 to 40xc2x0 C. to give compounds of Formulae (VIII) and (VIIIxe2x80x2). These compounds of Formulae (VIII) and (VIIIxe2x80x2) can be purified by a conventional separation method such as column chromatography.
(4) The compound of Formula (VIII) or (VIIIxe2x80x2) is mesylated or tosylated, for example, with 1 to 6 equivalents of methanesulfonyl chloride or p-toluenesulfonyl chloride in a proper solvent such as pyridine or toluene (if necessary, in the presence of 0.8 to 6 equivalents of a base such as triethylamine or 4-dimethylaminopyridine) at xe2x88x9220 to 40xc2x0 C., followed by chlorination with 1 to 16 equivalents of tetra-n-butylammonium chloride to give a compound of Formula (IX) or (IXxe2x80x2) wherein X is a chlorine atom, respectively. Herein, bromination or fluorination can be also carried out in an ordinary manner. For example, bromination can be carried out by a reaction using 1 to 10 equivalents of carbon tetrabromide in the presence of 1 to 10 equivalents of triphenylphosphine and 1 to 10 equivalents of pyridine in acetonitrile. Fluorination can be carried out, for example, by a reaction with 5 to 20 equivalents of diethylaminosulfur trifluoride (DAST) in methylene chloride.
(5) The tert-butyldimethylsilyl group of the compound of Formula (IX) or (IXxe2x80x2) is removed by using hydrofluoric acid, pyridinium poly(hydrogenfluoride) or hydrochloric acid in a solvent (e.g., methanol, ethanol, acetonitrile, a mixture thereof or a mixture of these solvent(s) and water) under conventional conditions to give a PG derivative of Formula (Ia) or (Iaxe2x80x2) of the present invention.
(6) The compound of Formula (Ia) or (Iaxe2x80x2) is hydrolyzed using 1 to 6 equivalents of a base in a conventional solvent for hydrolysis to give a PG derivative of Formula (Ib) or (Ibxe2x80x2) of the present invention. Examples of the base to be used are lithium hydroxide and potassium carbonate, and examples of the solvent to be used are acetonitrile, acetone, methanol, ethanol, water and a mixture thereof.
Furthermore, the compound of Formula (Ia) is hydrolyzed by a reaction with an enzyme in a buffer solution such as phosphate buffer or tris-hydrochloride buffer, if necessary, by using an organic solvent (e.g. a water-miscible solvent such as acetone, methanol or ethanol) to give a PG derivative (Ib) of the present invention. Examples of the enzyme to be used are enzymes produced by microorganisms (e.g. enzymes produced by microorganisms belonging to Candida sp. or Pseudomonas sp.) and enzymes prepared from animal organs (e.g. enzymes prepared from pig liver or pig pancreas). Commercially available enzymes are, for example, lipase VII (derived from microorganism of Candida sp.; Sigma Co.;), lipase AY (derived from microorganism of Candida sp.; Amano Pharmaceutical. Co.), lipase PS (derived from microorganism of Pseudomonas sp.; Amano Pharmaceutical Co.), lipase MF (derived from microorganism of Pseudomonas sp.; Amano Pharmaceutical Co.), PLE (prepared from pig liver; Sigma Co.). lipase II (prepared from pig pancreas; Sigma Co.) or lipoprotein lipase (prepared from pig pancreas; Tokyo Kasei Kogyo Co.).
The amount of the enzyme to be used, while depending on the potency of the enzyme and the amount of the substrate (the compound of Formula (Ia)), is usually 0.1 to 20 parts by weight based on the substrate, and the reaction temperature is from 25 to 50xc2x0 C., preferably 30 to 40xc2x0 C.
(7) The compound of Formula (Ia) or (Iaxe2x80x2) is oxidized using an oxidant such as sodium metaperiodate, hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid or tert-butyl hydroxyperoxide in diethyl ether, methanol, ethanol, methylene chloride, water or a mixture thereof at xe2x88x9220 to 50xc2x0 C. to give a PG derivative of Formula (Ic) or (Icxe2x80x2) of the present invention.
(8) The compound of Formula (Ic) or (Icxe2x80x2) is hydrolyzed in the similar manner as described in the above (6) to give a PG derivative of Formula (Id) or (Idxe2x80x2) of the present invention. In addition, the PG derivative of Formula (Ib) or (Ibxe2x80x2) is oxidized in the similar manner as described in the above (7) to give a PG derivative of Formula (Id) or (Idxe2x80x2) of the present invention.
Representative compounds of the present invention are described bellow.
The compounds of the present invention can be administered systemically or topically, or orally or parenterally (intravenously) in conventional dosage forms. For example, the dosage form for oral administration includes tablets, powders, granules, dusting powders, capsules, solutions, emulsions or suspensions, each of which can be prepared according to conventional methods. The dosage form for intravenous administration includes aqueous or non-aqueous solutions, emulsions, suspensions or solid preparations to be dissolved in a solvent for injection immediately before use. Furthermore, the compounds of the present invention can be formulated into the form of inclusion compounds with xcex1-, xcex2- or xcex3-cyclodextrin, or methylated cyclodextrin. In addition, the compounds of the present invention can be administered by injection in the form of aqueous or non-aqueous solutions, emulsions, suspensions, etc. The dose is varied by the age, body weight, etc., but it is from 1 ng to 1 mg/day per adult, which can be administered in a single dose or divided doses.